The invention in its broad aspects relates to phosphonic-aminoacid compounds and derivatives thereof which are useful as converting enzyme inhibitors and as antihypertensives. The compounds of this invention can be shown by the following formula: ##STR1## wherein
n is 0 or 1
R is hydrogen, lower alkyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, aminolower alkyl, guanidino lower alkyl, imidazoyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl mercapto lower alkyl;
R.sub.3 is hydrogen;
R.sub.4 is hydrogen, lower alkyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, aminolower alkyl, guanidino lower alkyl, guanidino lower alkyl, imidazoyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl mercapto lower alkyl;
R.sub.3 and R.sub.4 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms or an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom;
X is 0, NR.sup.5, S where R.sup.5 =H or lower alkyl;
R.sub.1 is hydrogen, lower alkyl, aralkyl or aryl;
R.sub.2 is hydrogen, lower alkyl, aralkyl or aryl and pharmaceutically acceptable salts thereof.
The lower alkyl groups represented by any of the variables include straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and the like. The aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxy benzyl and the like.
Aryl wherever it appears is represented by phenyl or substituted phenyl wherein the substituent is halo, lower alkoxy or lower alkyl.
The R and R.sub.4 substituted lower alkyl moieties are exemplified by groups such as ##STR2## HO--CH.sub.2 --, HS--CH.sub.2 --, H.sub.2 N--(CH.sub.2).sub.4 --, CH.sub.3 --S--(CH.sub.2).sub.2 --, H.sub.2 N--(CH.sub.2).sub.3 --, ##STR3## and the like.
R.sub.3 and R.sub.4 when joined through the carbon and nitrogen atoms to which they are attached may form a 4 to 6 membered ring which may contain one sulfur atom; a preferred ring has the formula: ##STR4## where Y is CH.sub.2 or S.
Preferred are those compounds of Formula I wherein
X=0, NR.sub.5 PA1 Y=CH.sub.2 or S; PA1 R=lower alkyl or phenyl (C.sub.1-4) alkyl; PA1 R.sub.1 and R.sub.2 are as previously defined; PA1 R.sub.3 and R.sub.4 are joined to form an alkylene bridge of from two to four carbon atoms or an alkylene bridge of from two to three carbon atoms and one sulfur atom but preferably where R.sub.3 and R.sub.4 are joined to form the preferred ring formula shown above. PA1 X=0 or NH and PA1 n=0.
Still more preferred compounds are those preferred compounds of Formula I wherein further R is methyl;
The products of Formula (I) and the preferred subgroups can be produced by one or more of the methods depicted in the following equations: ##STR5## Compound (II) is condensed with phosphorous oxychloride by the general method of T. Winnick and E. M. Scott, Arch. Biochem. 12, 201 (1947). ##STR6## R.sub.6 =alkyl or aralkyl.
Compound (V), an ester hydrochloride of compound (II), is condensed in an inert solvent such as methylene chloride with the phophochloridate diester (IV) in the presence of a base, such as triethylamine, to obtain the tri-ester (VI). Specific hydrolysis of the carboxylate ester group, as by base, affords the diester (VII; R.sub.1 and R.sub.2 do not equal H). Controlled removal of one of those ester groups, as by catalytic hydrogenolysis, with base, or with iodide salts by the method of L. Zervas, et al, J. Am. Chem. Soc. 77, 5354 (1955) yields the mono ester (VII; R.sub.1 is not equal to H, R.sub.2 =H). Alternately, compound (IV) may be condensed with compound (II) to afford compound (VII) directly. ##STR7## Then, when R.sub.1 =R.sub.2 =phenyl and R.sub.6 =t-butyl: ##STR8##
In this process, a 2-benzyloxy acetic acid derivative (VIII), which can be prepared from the corresponding 2-hydroxyacetic acid derivative, is reacted with thionyl chloride to produce the acid chloride (IX), which is then reacted with an ester (X) in a solvent such as methylene chloride containing a base, like triethylamine, to obtain the ester (XI). The ester is then converted to the hydroxy compound (XII) by use of hydrogen and a palladium catalyst in a conventional manner.
Alternately, compounds of structure XII may be obtained by coupling the unprotected hydroxy acetic acid derivative corresponding to VIII directly with the amino acid ester X by means of dicyclohexyl carbodiimide or a similar reagent. This hydroxy compound is reacted with a diaryl or diaryalkyl or dialkyl chlorophosphate in a solvent such as ether containing a base, like pyridine to yield the ester (XIII). When R.sub.1 =R.sub.2 =phenyl and R.sub.6 =t-butyl (XIII) is converted to the ester (XIV) by the use of hydrogen and a platinum catalyst in a conventional manner, and (XIV) is then converted to the acid (XV) by treatment with a strong acid, such as trifluoroacetic acid.
Alternately compound XII may be reacted with phosphorous oxychloride under basic conditions and hydrolyzed to obtain compound XV. ##STR9##
In this process, the bis-trichloroethyl ester (XVI) prepared as described above for (XII) is converted to the monotrichloroethyl ester (XVII) by a procedure described by K. K. Ogelvie, et al., J. Am. Chem. Soc. 99, 1277 (1977). The trichloroethyl function is then removed using a process described by A. Franke, et al., Chem. Ber., 101, 944 (1968). The ester (XVIII) is then hydrolyzed to (XIX) using standard procedures.
Alternatively, the hydroxy compound XII may be treated with an alkyl, aryl or aralkyl phosphodichloridate and hydrolyzed in aqueous base to obtain the mono-ester XIX. ##STR10## In this process, (XIII), prepared as described above, is hydrolyzed to the carboxylic acid derivative (XX) by a controlled basic hydrolysis. ##STR11##
In this process, a thiophosphoric acid derivative (XXI) is reacted with a bromo (or iodo) compound (XXII) in a process like that described by S. Akerfeldt, Acta Chem. Scand., 16, 1897 (1962).
Products of general Formula (I) have up to two asymmetric carbons, namely, the carbon atoms to which R and R.sub.4 are attached, when R and R.sub.4 are other than hydrogen. The compounds accordingly exist in diastereoisomeric forms or in racemic mixtures thereof. All of these are within the scope of the invention. The above described syntheses can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods.
In general, the amino acid part-structures, i.e., ##STR12## of Formula (I) are preferred in the L-configuration. These preferred configurations also apply to homolog amino acids and when X is 0 or S replacing NR.sub.5. Specifically when X is 0 or S the configuration is that of L-lactic or L-thiolactic acid respectively.
The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine and the like. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product, as illustrated in the examples in the case of the dicyclohexylamine salt.
The salts may be formed by conventional means, as by reacting the free acid form of the product with one or more equivalents of the appropriate base in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying, or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
The compounds of this invention inhibit angiotensin converting enzyme and thus block conversion of the decapeptide angiotensin 1 to angiotensin 2 and inhibit the degradation of bradykinin. Thus, the present compounds are useful as antihypertensives in treating hypertensive mammals, including humans.
The compounds of this invention can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of Formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as calcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.